Despite advances in therapy, greater than 90% of patients with multiple myeloma eventually relapse with chemotherapy-resistant disease. These myeloma cells are typically resistant to a wide range of chemotherapy agents through a number of different mechanisms, including upregulation of efflux pumps, mutations in drug targets and resistance to drug-induced apoptosis. It is therefore important to develop new treatment agents that are active against multi-drug resistant myeloma. Arsenic trioxide (As203) has been recently shown to have significant activity against relapsed acute promyelocytic leukemia. We have reported that As203 effectively induces apoptosis in vitro of both drug resistant myeloma cell lines and primary myeloma isolates from relapsed patients. Arsenic-induced apoptosis is triggered through the generation of reactive oxygen species (ROS) and subsequent oxidative cellular damage. We have also found that intracellular glutathione (GSH) protects against the toxicity of As203 (either by reducing ROS or by direct conjugation to arsenic). Addition of ascorbic acid (AA) depletes intracellular GSH and potentiates As203-mediated killing of chemotherapy-resistant myeloma cells. These data led us to open an NCI-sponsored phase I/II clinical trial of arsenic trioxide + ascorbic acid for the treatment of relapsed and refractory multiple myeloma. We have completed the phase I component, and have found that an As203 dose of 0.25 mg/kg/d + AA 1000 mg/d can be safely administered with modest toxicity and promising efficacy. Correlative studies demonstrate a significant association of serum ascorbic acid levels with depletion of intracellular GSH. Our hypothesis is that this combination will have activity against relapsed and refractory multiple myeloma, and propose a phase II clinical trial to determine the efficacy of arsenic trioxide + ascorbic acid in the treatment of relapsed/refractory myeloma. The central components of this proposal are correlative studies will seek to establish biochemical, cellular and genetic correlates of efficacy and toxicity. In addition, we will characterize potential mechanisms by which myeloma cells become arsenic resistance, the effect of this resistance on responses to other drugs, and approaches to overcome this resistance.